The skin is a multi-layered structure made up of stratum corneum, under which lies the epidermis and dermis. The dermis contains blood vessels as well as nerves and nerve endings which are sensitive to touch and pain. The barrier structure of the stratum corneum makes the stratum corneum about 1000 times less permeable than other biological membranes and presents a major challenge for transdermal delivery of active pharmaceutical ingredients to the dermis (Aute et al. International Journal of Research and Development in Pharmacy and Life Sciences, Vol. 2 (1), pp. 218-224, 2012).
Permeation of a drug through skin can be enhanced by both chemical penetration enhancement and physical methods (Pathan and Setty, Trop J Pharm Res, Vol. 8 (2) p. 173, 2009). One method of enhancing skin penetration of active pharmaceutical ingredients (APIs) is by encapsulating the API in an ethosome. Ethosomes comprise mainly alcohol, water and phospholipid, and were previously described by Touitou et al. (Journal of Controlled Release, Vol. 65, pp. 403-418, 2000, U.S. Pat. No. 5,716,638). Touitou et al. demonstrates that ethosomal systems are more efficient at delivering a fluorescent probe to the skin in terms of quantity and depth than either liposomes or hydroalcoholic solutions.
Ethosomes have also been found to have a high entrapment capacity for molecules of various lipophilicities, and to be capable of encapsulating hydrophilic drugs, cationic drugs, proteins and peptides. Some examples of drug molecules that have been formulated with ethosomes for transdermal delivery are cannabinoids, testosterone, minoxidil, propranolol, trihexaphenidyl, zidovudine, bacitracin, erythromycin, acyclovir, methotrexate, cyclosporine, insulin and salbutamol (Akiladevi, D. et al. International Journal of Current Pharmaceutical Research, Vol. 2, Iss. 4, 2010; Aute et al. International Journal of Research and Development in Pharmacy and Life Sciences, Vol. 2, No. 1, pp 218-224, December-January, 2012-13).
It has been suggested that the relatively high concentration of ethanol (20-50%) in vesicular form in ethosomes is the main reason for their good skin permeation ability, and that ethanol acts to disturb the skin lipid bilayer organization. The presence of ethanol in the ethosome also yields a softer and malleable vesicle structure, which gives more freedom, elasticity and stability to its membrane. The ethosomal transdermal drug delivery system has been reported to improve skin delivery of various drugs in vitro and in vivo (Zhang, J-P. et al., Archives of Pharmacal Research, Vol. 35(1), pp. 109-117, 2012). Some benefits of using ethosomes in particular as a transdermal drug delivery carrier include: deep penetration of the medication; penetration through skin to reach muscles and deep nerves where the pain can be successfully treated; safe ingredients; easy to apply; dries quickly with no mess; starts to work in minutes; and long lasting effects.
Transdermal formulations can be used to treat pain and inflammation that is of soft tissue in origin. This can be due to injury to tendons, ligaments, muscles and joints, such as sprains and strains, as well as due to neurological issues caused by soft tissue rheumatism and osteoarthritis in peripheral joints such as those in the knee or hand. Muscle pain is often due to focal muscular contraction or contraction at a trigger point.
Magnesium cation (Mg2+) has been shown to have inhibitory action on the release of Ca2+ from the sarcoplasmic reticulum in skeletal muscles, and increased amounts of magnesium near muscles has been shown to result in relaxation of the muscle (Jump, T., Sherwood, L. Human Physiology West Publ Co. Minneapolis USA 1993; Smith, J. S. et al. Journal of General Physiology Vol. 88, pp. 573-588, 1986). The effect of local action of magnesium on skeletal muscles is as a topical muscle relaxant, by blocking calcium from entering the muscle to cause contraction (Laver, D. R. et al. The Journal of Membrane Biology Vol. 156, pp. 213-229, 1997). Magnesium is also essential for the formation of ATP that is needed to cause the relaxation of the muscle and the exocytosis of calcium from muscle fibre cells. Magnesium also acts on the glutamate receptor which has been implicated in numerous neurological disorders. Increasing local magnesium concentration near neurons has also been found to block the transmission of action potential to the muscles by calcium-gated ion channel, and also to block N-methyl-D-aspartate (NMDA) receptors, which are a kind of glutamate receptor. Magnesium has been found to be a natural block for the NMDA receptor. In blood vessels, locally high levels of magnesium have also be shown to act as calcium channel blockers to causes blood vessel dilatation, which can lead to improved local circulation. Better circulation means more blood to an area of pain or injury, which can provide additional physiological support and energy for healing. Magnesium has also been found to have inhibitory activity on Ryanodine receptors, which are receptors involved in muscle contraction. However, it has been found that direct application of magnesium cation on the skin, even in high concentrations, does not result in any significant skin penetration (Eisenkraft et al. Military Medicine Vol. 174(1), pp. 47-52, 2009).
The vanilloid receptor (TRPV1) is one of six sub-members that belong to the transient receptor potential channel (TRP) superfamily. TRPV1 is a non-selective cation channel permeable for calcium found on nociceptors that provides the sensation of scalding heat and pain. Activation of TRPV1 sets off an influx of calcium and sodium ions which in turn initiates a cascade of events that result in membrane depolarization, neuronal firing and transduction of neural impulses. TRPV1 exhibits two types of desensitization: acute desensitization, which is the diminished response during a constant agonist application, and tachyphylaxis, which is the reduction of the response to multiple stimuli (Xu et al. The Journal of Neuroscience 25(39):8924-8937, 2005).
Capsaicin is a naturally occurring vanilloid which acts as an agonist to TRPV1. Capsaicin has demonstrated positive effects in the treatment of nociceptive pain, such as arthritis, and neuropathic pain, such as diabetic foot. Resiniferatoxin (RTX) and allyl isothiocyanate are other naturally occurring compounds that exhibit TRPV1 agonistic activity. However, delivery of capsaicin and other TRPV1 agonists, or TRPV1 antagonists to the TRPV1 receptor has proven challenging, especially because even small doses of these compounds can cause perceptible and sometimes intolerable burning sensation to the skin.
There remains a need for a transdermal composition for the treatment of pain.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.